This invention relates to the production of bis(arene)technetium complexes suitable for intravenous use in the radiodiagnosis of certain pulmonary and coronary metabolic functions.
Bis(arene)technetium complexes are of great practical clinical interest particularly in the diagnostic imaging of myocardial uptake. These compounds accumulate in normal heart tissue, as opposed to infarcted tissue, and the gamma rays emitted therefrom allow for the early identification of individuals at high risk of having heart attacks. An image of the heart tissue, taken for example with a scintillation camera, can be made inexpensively and expediantly. See co-pending U.S. application Ser. No. 739,511 filed May 31, 1985 by Wester et al.
However, the production of bis(arene)technetium complexes generally have received only cursory attention in the literature, usually being prepared for comparative studies with analagous manganese or rhenium compounds. The preparations of cyclopentadienyl and benzene derivatives were reported as early as 1961 (Huggins, D. K. and Kaesz, H. D., J. Amer. Chem. Soc., 83:4474 [1961]; Fischer, E. O. and Schmidt, M. W., Chem. Ber., 100:3782 [1967]; Baumgartner, F. et al., Chem. Ber., 94:2198 [1961]; Palm, C. et al., Tet. Lett., 1962(6) 253). Preparation of a hexamethylbenzene derivative was described by Fischer, E. O. and Schmidt, M. W., Chem. Ber., 102:1954 (1969). Since that time the compounds have received no further attention in the literature.
Synthetic routes to the benzene and hexamethylbenzene complexes of technetium-99, as reported in the prior art, are long and arduous, making them unacceptable for commercial use. The prior art procedures generally use technetium tetrachloride (TcCl.sub.4) as a starting material, a substance which is not easily prepared from Mo-99/Tc-99m generators. In the prior art procedures, TcCl.sub.4 and benzene or hexamethylbenzene (along with other reagents) are heated in a sealed tube for 3 days or 24 hours, respectively. Since the half life of Tc-99m is 6 hours, it is apparent that most of the Tc-99m obtained from a generator will have decayed in the time required to prepare a technetium-arene complex by the prior art processes. More importantly, the partially methylated bis(arene) technetium complexes derived from starting materials such as pentamethylbenzene or tetramethylbenzene will undergo severe disproportionation into undesired impurities of other partially methylated benzenes at a rate as high as 30% or greater. This disproportionation or isomerization of the methylbenzenes occurs in the presence of aluminum chloride which is a necessary Fischer reactant. For example, when starting with pentamethylbenzene, both tetramethyl- and hexamethylbenzene are found in the reaction mixture in substantial amounts, indicating disproportionation or a isomerization of methyl groups during the reaction. The degree of disproportionation is believed to be virtually independent of the amount of aluminum chloride present, however. The disproportionation also occurs in the presence of aluminum powder and hydrogen chloride which are alternatives to the use of aluminum chloride although equivalent for purposes of this discussion. Previously, it was postulated that the presence of zinc and hydrogen chloride would diminish if not eliminate the disproportionation; however, in the presence of heat, improvements are still desired. Accordingly, it would be a substantial advancement in the art to prepare bis(arene)technetium complexes particularly the partially methylated variety at desirable high ratios of Tc-99m/Tc-99 of improved purity without disproportionation which are in turn of great practical clinical utility as radiodiagnostic imaging agents using the procedures of the prior art.